Non-Neoplastic and Neoplastic Pathology of the Pancreas

Pancreas Divisum

Pancreas divisum occurs in 3% to 7% of the population as a result of failure of the embryonic dorsal and ventral pancreatic buds to fuse properly. The duct of Santorini becomes the major ductal system of the pancreas, and it drains into the duodenum through the diminutive minor papilla. The small size of the minor papilla relative to the substantial flow through the major duct impedes the flow of pancreatic secretions and, in some patients, produces pancreatitis. Endoscopic retrograde cholangiopancreatography can be used to demonstrate the abnormal ductal anatomy and to exclude other causes of the patient’s symptoms.

Pancreas divisum is best appreciated through careful gross dissection of the duct system. Imaging of a resected pancreas after the injection of a radiopaque dye into the duct system can also be used to establish the diagnosis. It is often associated with chronic pancreatitis, but the microscopic appearance is etiologically nonspecific. The differential diagnosis includes other causes of pancreatitis. Sphincterotomy of the minor papilla has been used to treat some patients with mixed results. The prognosis is dependent on the severity of pancreatitis.

Annular Pancreas

Annular pancreas is a rare malformation in which the dorsal and ventral buds of the pancreas abnormally fuse, forming a ring of pancreatic parenchyma around the duodenum. This ring can cause duodenal obstruction later in life. Most patients present clinically at a young age (∼1 year), but some do not develop symptoms until adulthood. Children with annular pancreas can present with vomiting after meals and abdominal distention. Abdominal radiographs may show a classic “double-bubble” sign of intestinal obstruction.

A careful dissection of the resected specimen and clinical correlation with preoperative imaging studies and findings at surgery is the best way to establish the diagnosis. The differential diagnosis includes other causes of obstruction such as pyloric stenosis, ectopic pancreas, and duodenal atresia. Surgical resection of the obstruction is the treatment of choice, with an excellent prognosis after surgery.

Ectopic Pancreas

Pancreatic parenchyma located outside of the normal pancreas is referred to as ectopic pancreas. Ectopic pancreas is found in 2% of the population. Although ectopic pancreas is usually an incidental finding, it can cause bleeding and, in rare instances, intestinal obstruction. Ectopic pancreas only rarely forms a mass large enough to be detected radiographically. The upper gastrointestinal tract (stomach, duodenum, jejunum) is the most common location of ectopic pancreas. Other sites include ileum and Meckel’s diverticulum ( Fig. 16.1 ). These foci are composed of collections of normal acini and ducts and frequently islets of Langerhans. Surgical resection is the treatment of choice in symptomatic patients and is usually curative.

Simple Mucinous Cyst

Simple mucinous cysts are larger than 1 cm in size, lined by flat mucinous gastric type epithelium with minimal atypia, and lack ovarian-type stroma ( Fig. 16.4 ). Depending on the features of the surrounding pancreatic tissue, different terms have been used to address these cysts. In case of an obstruction of the pancreatic duct, these cysts have been interpreted as retention cysts with partial pancreatic intraepithelial neoplasia 1 (PanIN-1) lining. Terms such as mucinous non-neoplastic cyst and cystic mucinous duct lesion have been used for lesions not associated with an obstructive process. Simple mucinous cysts can carry Kras mutations and even high-grade dysplasia in keeping with a neoplastic process.

Congenital Cyst

Congenital cysts are usually 1 to 2 cm in diameter and do not communicate with the duct system. These cysts have a paucicellular fibrous wall and are lined by cuboidal epithelium resembling the lining of normal ducts. The epithelium can be flattened and atrophic, and squamous epithelium is sometimes present. These cysts are mostly solitary but may be multiple when associated with cysts of the kidney and liver. Congenital cysts are most often found in children. In adults, congenital cysts are indistinguishable from retention cysts.

Duodenal Diverticulum

A duodenal diverticulum on the pancreatic side of the duodenum can appear as a unilocular intrapancreatic or peripancreatic cyst and mimic a pancreatic cyst. Duodenal diverticula communicate with the duodenal lumen, in contrast to enteric duplication cysts, which do not communicate with the duodenal lumen and are most often lined by gastric mucosa. Duodenal diverticula are composed of small intestinal mucosa, which may cause confusion with intestinal-type IPMN ( Fig. 16.5 ).

Clinical Features

Acute pancreatitis affects approximately 20 individuals per 100,000 population each year in Western nations. Most cases are caused by alcohol abuse or biliary tract disease. Other risk factors are smoking and genetic predisposition. Patients present with epigastric pain that radiates to the back and elevated serum amylase levels. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis, infections, and pseudocyst.

Radiologic Features

Ultrasonography and CT reveal diffuse enlargement of the gland.

Pathologic Features

The pancreas is usually enlarged and soft, and the pancreatic and peripancreatic fat contains chalky white foci of fat necrosis. Severe cases may show hemorrhage into the gland. Microscopic findings range from mild edema with scattered inflammatory cells to extensive necrosis and hemorrhage ( Fig. 16.6 ).

Ancillary Studies

Elevated serum amylase levels support the diagnosis.

Differential Diagnosis

The differential diagnosis for acute pancreatitis is narrow and includes recurrent chronic pancreatitis. Clinical history is essential for making this distinction.

Prognosis and Therapy

Acute pancreatitis has an overall low mortality rate of approximately 1%, but this varies with the severity. Several scoring systems (Ranson’s criteria, APACHE-II, BiSAP, Marshall score) are used to predict the prognosis of patients with pancreatitis. The treatment of patients with acute pancreatitis primarily consists of “resting” the pancreas and supportive care. Approximately 20% to 30% of patients with acute pancreatitis have a recurrence, and approximately 10% develop chronic pancreatitis. Progression from acute to chronic pancreatitis occurs more frequently in patients with continued alcohol and tobacco use and in patients with hereditary pancreatitis.

Clinical Features

Patients with chronic pancreatitis present with abdominal pain; exocrine and endocrine insufficiency, including diabetes mellitus and malabsorption with steatorrhea; and weight loss. Most cases in Western countries are caused by chronic alcohol abuse. In addition, obstruction of the pancreatic duct from ductal stones, tumors, strictures, or anatomical anomalies such as pancreas divisum can also cause chronic pancreatitis. A minority of patients have an inherited syndrome, including familial pancreatitis caused by mutations in PRSS1 or SPINK1 or cystic fibrosis.

Radiologic Features

Calcifications within the pancreas can be visualized on plain abdominal radiographs. Ultrasonography demonstrates ductal dilation; CT shows an atrophic pancreas with calcifications and small cysts.

Pathologic Features

Chronic pancreatitis is characterized by an inflammatory cell infiltrate associated with replacement of the normal pancreatic parenchyma with fibrous connective tissue ( Fig. 16.7 ). This loss of acinar tissue can be associated with dilation of the pancreatic ducts and intraductal inspissated secretions. The islets of Langerhans are relatively spared, with evidence of islet cell aggregation in some cases. The inflammatory cell infiltrate is usually composed of a mixture of lymphocytes, plasma cells, and scattered neutrophils.

Ancillary Studies

None are needed.

Differential Diagnosis

The atrophic glands of chronic pancreatitis can mimic a well-differentiated infiltrating adenocarcinoma. Features that favor a reactive process over a neoplastic process include retention of normal lobular architecture of the acini, glands with complete lumina, absence of luminal necrosis, and only mild nuclear pleomorphism. Perineural and vascular invasion, when present, are diagnostic of invasive adenocarcinoma.

Prognosis and Therapy

Patients with chronic pancreatitis have shorter survival times than the general population, but most die from nonpancreatic causes, such as other chronic diseases, cancers, or infections. Chronic pancreatitis, particularly young onset and hereditary pancreatitis, also increases risk of pancreatic cancer. Treatment is mostly supportive, with pancreatic exocrine enzyme replacement and careful management of diabetes and pain. Endoscopic intervention is indicated for ductal stones, main pancreatic duct strictures, and symptomatic pseudocysts. Indications for surgical intervention include poorly controlled pain, symptomatic pseudocysts, and suspicion of malignancy.

Clinical Features

Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis in which patients present with obstructive jaundice, imaging findings mimic pancreatic cancer, and conventional risk factors for pancreatitis such as alcoholism are lacking. Two subtypes of AIP with different histopathologic and clinical characteristics are recognized. Type 1 AIP, also called lymphoplasmacytic sclerosing pancreatitis, is a disorder in the spectrum of immunoglobulin (Ig) G4–related diseases. Type 1 AIP most often affects men, with a male-to-female ratio of approximately 3 to 1. The mean age of diagnosis is 60 years or older. Serum IgG4 levels are elevated in most patients, and extrapancreatic involvement, such as proximal bile duct strictures, retroperitoneal fibrosis, or bilateral salivary gland enlargement, is seen in about half of these patients. IgG4 elevation is variably defined depending on the laboratory, and levels greater than 135 mg/dL, greater than 121 mg/dL, or greater than 86 mg/dL have all been reported as cutoffs in the literature. Type 2 AIP, also called idiopathic duct-centric chronic pancreatitis , occurs in patients between 40 and 50 years of age. Men and women are equally affected. About 25% of patients have concurrent inflammatory bowel disease, and patients typically do not have elevated serum IgG4 levels.

Radiologic Features

Type 1 and type 2 AIP are radiologically indistinguishable. About 30% to 50% of patients show the classic radiologic appearance of a diffuse enlargement of the gland with loss of the normal lobulated contour, the so-called “sausage-shaped pancreas.” Alternatively, focal or multifocal enlargement of the pancreas can be seen.

Pathologic Features

Type 1 and type 2 AIP are indistinguishable on gross examination. Most cases show diffuse enlargement of the pancreas, although localized “pseudotumor” or discrete nodules can also be seen ( Fig. 16.8 ). International consensus histopathologic diagnostic criteria have been formulated that distinguish AIP from other forms of chronic pancreatitis and distinguish type 1 AIP from type 2. Periductal lymphoplasmacytic infiltrate and an inflammatory cellular stroma are the key diagnostic features of both types of AIP that distinguish AIP from other types of chronic pancreatitis. Storiform fibrosis, obliterative phlebitis, and lymphoid follicles are also typically seen in type 1 AIP. Obliterative phlebitis is often best seen at the interface between diseased and normal tissues ( Fig. 16.9A ). Marked pancreatic acinar atrophy is often associated with a brisk myofibroblastic proliferation in a storiform pattern ( Fig. 16.9B ). Importantly, although type 1 AIP typically shows marked infiltration by IgG4+ plasma cells of greater than 10 per hpf, this is not a specific finding for type 1 AIP and should only be used as an adjunct to support the diagnosis ( Fig. 16.9C ). Granulocytic epithelial lesions are pathognomonic for type 2 AIP and are characterized by aggregates of neutrophils within the ductal epithelium and lumen ( Fig. 16.10 ). In addition, neutrophilic infiltration in surrounding acinar tissue may be present.

Ancillary Studies

International consensus diagnostic criteria for AIP and to differentiate between type 1 and type 2 include five cardinal features of AIP, which are imaging, serology, other organ involvement, histology of the pancreas, and response to steroid therapy. A diagnostic steroid trial can be considered to confirm a strong suspicion of AIP. Serum IgG4 levels are elevated in most patients with type 1 AIP, and this finding can be used to support a preoperative diagnosis.

Differential Diagnosis

The differential diagnosis includes other forms of pancreatitis and pancreatic cancer in cases of focal mass on imaging. Duct-centric lymphoplasmacytic infiltrates, with or without granulocytic lesions, increased IgG4 positive plasma cells, inflamed stroma with storiform fibrosis, and obliterative phlebitis are features that favor a diagnosis of AIP. In contrast, ectatic ducts with inspissated secretions, marked acute inflammation within acinar or interlobular stroma, fat necrosis, and dense hyaline fibrosis involving intra- and interlobular stroma are suggestive of chronic obstructive pancreatitis rather than AIP. Differentiating type 2 AIP from acute on chronic pancreatitis not otherwise specified can be challenging and should be done in correlation with clinical findings.

Prognosis and Therapy

Autoimmune pancreatitis is important to recognize because it can clinically mimic pancreatic cancer. Both type 1 and type 2 AIP respond well to steroid therapy, and type 1 AIP also responds to rituximab. Type 1 AIP frequently relapses, whereas relapses are uncommon in type 2. Both types of AIP have excellent long-term survival rates.

Paraduodenal (Groove) Pancreatitis

Pathologic Features

Paraduodenal pancreatitis, in addition to arising in a very specific region, has a characteristic microscopic appearance. The cysts, which may contain inspissated secretions and degenerated polymorphonuclear cells, are lined by partially or completely denuded ductal epithelium and are often surrounded by granulation tissue ( Fig. 16.11 ). In addition, pseudocysts can be present. A reactive spindle cell proliferation is often present, which may be very prominent, raising suspicion of leiomyoma or gastrointestinal stromal tumor. Almost all cases show Brunner’s gland hyperplasia, which is largely responsible for the thickening and polypoid appearance of the duodenal mucosa.

Clinical Features

Pseudocysts are localized collections, usually extrapancreatic, of necrotic material rich in pancreatic enzymes that account for 75% of all pancreatic “cysts.” They usually develop after an episode of acute pancreatitis or after trauma to the pancreas. Patients often have a severe epigastric pain that radiates to the back. In the United States, most patients have a history of heavy alcohol consumption.

Radiologic Features

Abdominal imaging shows a unilocular cystic mass.

Pathologic Features

Pseudocysts are usually solitary and extrapancreatic and filled with necrotic or hemorrhagic material. They do not have an epithelial lining and are lined by variably inflamed granulation tissue and necrotic debris ( Fig. 16.12 ).

Ancillary Studies

Aspirates of pseudocysts show abundant thin and watery, turbid, and sometimes hemorrhagic fluid, which is rich in lipase and amylase and low in carcinoembryonic antigen (CEA) levels.

Differential Diagnosis

The differential diagnosis of a pseudocyst includes retention cyst, serous cystadenomas (SCAs), MCN, IPMN, SPN, and cystic change in a usually solid pancreatic neoplasm. The absence of an epithelial lining combined with necrotic or hemorrhagic cyst contents rich in lipase and amylase establish the diagnosis of a pseudocyst.

Prognosis and Therapy

Most pseudocysts resolve with supportive care, but some require surgical drainage. Superinfection of a pseudocyst is a serious complication.

Precursor Lesions

The following lesions are currently considered to be precursors to ductal carcinoma of the pancreas and its variants: PanIN, IPMN, intraductal oncocytic papillary neoplasm, MCN, and intraductal tubulopapillary neoplasm (ITPN).

Pancreatic Intraepithelial Neoplasia

Pathological Features

Pancreatic intraepithelial neoplasia typically involves the epithelium of intra- and interlobular ducts that are smaller than 5 mm in diameter, but the main pancreatic duct may also be involved in some cases. By definition, the lesions are not visible grossly unless the ducts get dilated because of obstruction or some other mechanisms. PanIN is classified into low (previous PanIN-1 and PanIN-2 categories) and high grade (previous PanIN-3 category). Low-grade PanIN is characterized by a flat or papillary or micropapillary proliferation of tall columnar epithelial cells with abundant intracytoplasmic mucin and basally located round to oval nuclei. Nuclear atypia varies from none to mild nuclear crowding, enlargement, pseudostratification, and hyperchromasia. Mitoses are rare, and when present, they are not atypical ( Fig. 16.13A ). Conversely, high-grade PanIN is usually papillary/micropapillary and is characterized by cribriforming, budding, luminal necrosis, and irregular nuclei with visible nucleoli and frequent mitoses ( Fig. 16.13B ).

Importantly, PanIN harbors many of the same genetic alterations seen in PDAC. Although the genetic alterations do not occur in a specific sequence, their prevalence tends to increase from low to high grade. Whereas telomere shortening and activating mutations in codon 12 of the KRAS gene occur early in low-grade PanIN, inactivating mutations in the p16/CDKN2A gene tend to be seen in low-grade PanIN with more significant cytomorphologic atypia. SMAD4 and TP53 mutations usually occur in high-grade lesions. In addition, hypermethylation of several genes, including p16 , has been reported, and the prevalence of hypermethylation increases from low- to high-grade PanIN.